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Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = \u22120.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad166","type":"journal-article","created":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T04:03:54Z","timestamp":1684555434000},"source":"Crossref","is-referenced-by-count":9,"title":["Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8620-9531","authenticated-orcid":false,"given":"Emmet","family":"Costello","sequence":"first","affiliation":[{"name":"Academic Unit of Neurology, Trinity Biomedical Science Institute , Dublin D02 R590 , Ireland"},{"name":"Psychology Department, Beaumont Hospital , Dublin D09 V2N0 , 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D02 R590 , Ireland"},{"name":"Psychology Department, Beaumont Hospital , Dublin D09 V2N0 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Doherty","sequence":"additional","affiliation":[{"name":"Academic Unit of Neurology, Trinity Biomedical Science Institute , Dublin D02 R590 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3915-2135","authenticated-orcid":false,"given":"Russell Lewis","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Academic Unit of Neurology, Trinity Biomedical Science Institute , Dublin D02 R590 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"McHutchison","sequence":"additional","affiliation":[{"name":"Human Cognitive Neurosciences\u2013Psychology, School of Philosophy, Psychology, Language Sciences, The University of Edinburgh , Edinburgh EH8 9AD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Abrahams","sequence":"additional","affiliation":[{"name":"Human Cognitive Neurosciences\u2013Psychology, School of Philosophy, Psychology, Language Sciences, The University of Edinburgh , Edinburgh EH8 9AD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh , Edinburgh EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Heverin","sequence":"additional","affiliation":[{"name":"Academic Unit of Neurology, Trinity Biomedical Science Institute , Dublin D02 R590 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"Hardiman","sequence":"additional","affiliation":[{"name":"Academic Unit of Neurology, Trinity Biomedical Science Institute , Dublin D02 R590 , 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